Abstract
Information processing speed is a core cognitive process, highly relevant in everyday life and the most frequent and disabling cognitive symptom in patients with relapsing multiple sclerosis. Correlational evidence from brain imaging suggests involvement of the superior parietal lobe in the speed component of information processing, thereby providing a neurobiological foundation for neuromodulatory interventions. By using regionally specific, focalized transcranial direct current stimulation (tDCS) in healthy individuals and patients with relapsing multiple sclerosis, we provide causal evidence for superior parietal lobe involvement in information processing speed and identified a clinically relevant predictor of tDCS response in patients with relapsing multiple sclerosis. The study employed a registered, randomized, sham tDCS-controlled, three-way-blinded, cross-over trial and a mixed-factors design with eight arms [between-subjects: group (patients/healthy controls; N = 32/group); tDCS polarity (excitatory/inhibitory); within-subjects: stimulation (active/sham tDCS)]. Concurrently with tDCS (1.5 mA; active: 20 min; sham: 40 s), participants completed a computerized version of the Symbol Digit Modalities Test, the current gold standard for quantifying information processing speed impairment in patients with relapsing multiple sclerosis. Data were analysed in a Bayesian framework with generalized linear mixed models. Bayesian modelling provided strong causal evidence of bilateral superior parietal lobe involvement in information processing speed and a double dissociation of stimulation response in patients and controls (i.e. a significant three-way interaction of group × stimulation × polarity). Healthy individuals showed the expected canonical pattern of significantly reduced and increased response latency during anodal or cathodal tDCS, respectively. Across the patient groups, a reversed pattern was found and tDCS response was predicted by baseline Symbol Digit Modalities Test performance. More impaired patients benefited from cathodal tDCS, while less impaired patients benefited from anodal tDCS. For standardized Symbol Digit Modalities Test scores, the transition from beneficial to non-beneficial effects (anodal: < -0.58; cathodal: > -0.70) was consistent across the patient groups. tDCS was well tolerated, with no evidence for differences in mild adverse effects across groups and tDCS conditions. Blinding integrity was confirmed and behavioural outcomes were not explained by factors unrelated to tDCS. Our results provide direct causal evidence for superior parietal lobe involvement in information processing speed in health and disease and suggest that the degree of information processing speed impairment in the patients reflects compensatory or dysfunctional neuroplastic processes that can be counteracted by tDCS in a polarity-specific way. Identified standardized transition scores for the effectiveness of excitatory or inhibitory tDCS will inform future individually tailored stimulation protocols in patients with relapsing multiple sclerosis (trial registration: NCT04667221).